Ibrutinib plus venetoclax for previously treated CLL: CLARITY trial

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Published: 10 Dec 2017
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Prof Peter Hillmen - University of Leeds, Leeds, UK

Prof Hillmen speaks with ecancer at the 2017 ASH annual meeting about the CLARITY trial looking at ibrutinib plus venetoclax in relapsed, refractory CLL

Read the news story and watch the press conference for more. 

ecancer's filming has been kindly supported by Amgen through the ECMS Foundation. ecancer is editorially independent and there is no influence over content.

I chair the NCRI CLL subgroup for the UK and what I’ve presented is the first data in terms of response of a novel combination therapy for chronic lymphocytic leukaemia, or CLL. So we combined the two most effective drugs that have recently been approved as single agents – ibrutinib, which inhibits the proliferation of the disease, and venetoclax, which encourages the cells to apoptosis or to undergo cell death. So those two pathways are critical to CLL pathophysiology so they’re a logical combination to explore.

What did you do? What did you look at?

We recruited a total of fifty patients to the combination therapy. These were patients with CLL who had failed previous therapies. The majority had had chemoimmunotherapy, our most effective front line treatment, other patients had had targeted treatments if they weren’t eligible for chemotherapy. We then treated them with a two month period of ibrutinib to reduce the bulk of disease and then added venetoclax, the apoptotic drug, to try and eradicate detectible disease. What we’re reporting at this meeting is the first six month marrows and assessment of response after six months of the combination showing really very high response rates, in fact every patient has responded and almost half the patients had a complete response. In about a third, just under a third, we have minimal residual disease negative so we can’t detect by conventional flow tests disease in the marrow or blood.

Before we get into the impact can you talk a bit about the adverse events that you’re finding?

We know that despite ibrutinib and venetoclax both being targeted treatments rather than chemotherapy they do have specific side effects themselves. So for ibrutinib the most common side effects really are bruising and gastrointestinal – diarrhoea, usually mild but can be sometimes difficult to control – and for venetoclax really some gastrointestinal toxicity but tumour lysis syndrome works too effectively initially and also low neutrophils, which is usually manageable. So we’re obviously watching those things very closely. What we found was there was really no additional toxicity that we weren’t expecting. We only had a single case of tumour lysis syndrome which was easily managed which is what we would expect with fifty patients on venetoclax anyway. We saw neutropenia but, again, that didn’t lead to stopping of therapy and was manageable with our conventional supportive care and some gastrointestinal toxicity which was virtually all grade 1 or grade 2, so relatively manageable for most patients.

The potential impact of this research so far?

So the impact really is that we have demonstrated that this combination is safe and we’ve demonstrated that it’s more effective than we were targeting. So obviously when we do trials we have an expectation for how effective it’s going to be and our expectation was we wanted to see at least 30% of patients MRD negative after twelve months of combination. So we’ve already achieved that after six months of combination is obviously very encouraging and the fact that every patient has responded. One of the important parts of the UK really now and what we’re doing in the UK, is linking these phase II trials to our front line phase III programme so we’re haven’t got a big delay before we have trials that will really change practice. So we’ve already moved, actually several months ago, the combination, because we knew it was safe then, into our front line trial which will prove definitively whether this combination is better than chemotherapy in front line and single agent targeted therapy.

And you’ll be looking at this in terms of follow-up as well a long way in the future?

The CLARITY study, the study I presented today, we’ll be looking at the 12 month and 24 month time points. It’s fully recruited, the trial, although with the Trials Association Programme which Bloodwise fund we have the facility to add more cohorts of patients with more drugs. So, for example, we’re planning potentially to add another cohort of patients with a third drug added to the combination to see if we can achieve even higher and quicker eradication of detectable disease with the possibility of that feeding into our phase III programme.